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MicroRNA-124 and -137 cooperativity controls caspase-3 activity through BCL2L13 in hippocampal neural stem cells.

Schouten M, Fratantoni SA, Hubens CJ, Piersma SR, Pham TV, Bielefeld P, Voskuyl RA, Lucassen PJ, Jimenez CR, Fitzsimons CP - Sci Rep (2015)

Bottom Line: Adult neurogenesis continuously contributes new neurons to hippocampal circuits and the programmed death of a subset of immature cells provides a primary mechanism controlling this contribution.However, a possible interplay between this factors remains largely unexplored.Within these networks, we report for the first time that the atypical BCL2 protein BCL2L13 controls caspase-3 activity and cytochrome C release in neural stem/progenitor cells.

View Article: PubMed Central - PubMed

Affiliation: Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, SciencePark 904, 1098XH, Amsterdam, The Netherlands.

ABSTRACT
Adult neurogenesis continuously contributes new neurons to hippocampal circuits and the programmed death of a subset of immature cells provides a primary mechanism controlling this contribution. Epileptic seizures induce strong structural changes in the hippocampus, including the induction of adult neurogenesis, changes in gene expression and mitochondrial dysfunction, which may all contribute to epileptogenesis. However, a possible interplay between this factors remains largely unexplored. Here, we investigated gene expression changes in the hippocampal dentate gyrus shortly after prolonged seizures induced by kainic acid, focusing on mitochondrial functions. Using comparative proteomics, we identified networks of proteins differentially expressed shortly after seizure induction, including members of the BCL2 family and other mitochondrial proteins. Within these networks, we report for the first time that the atypical BCL2 protein BCL2L13 controls caspase-3 activity and cytochrome C release in neural stem/progenitor cells. Furthermore, we identify BCL2L13 as a novel target of the cooperative action of microRNA-124 and microRNA-137, both upregulated shortly after seizure induction. This cooperative microRNA-mediated fine-tuning of BCL2L13 expression controls casp3 activity, favoring non-apoptotic caspase-3 functions in NSPC exposed to KA and thereby may contribute to the early neurogenic response to epileptic seizures in the dentate gyrus.

No MeSH data available.


Related in: MedlinePlus

Significantly overrepresented networks containing dysregulated proteins in the DG after KA-SE.(A) SON depicting nodes around NFkB, including CLU and other upregulated proteins. (B) SON depicting nodes around FOS, including GFAP and other significantly upregulated proteins. (C) SON depicting nodes around NFkB, including BAX and other significantly downregulated proteins. (D) SON depicting nodes around TNF including BCL2L13 and other significantly downregulated. Gene products (nodes) are represented as standard IPA polygons and relationships with lines (edges) between nodes. Full lines indicate a direct interaction and dashed lines an indirect interaction. Intensity of the node color indicates the degree of regulation (SAL vs. KA) and relationship strength is inversely related to line length. Genes represented by uncolored nodes were not differentially expressed in our experiments and were integrated by the IPA knowledge database. Arrows represent activation while non-arrowed lines binding only.
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f2: Significantly overrepresented networks containing dysregulated proteins in the DG after KA-SE.(A) SON depicting nodes around NFkB, including CLU and other upregulated proteins. (B) SON depicting nodes around FOS, including GFAP and other significantly upregulated proteins. (C) SON depicting nodes around NFkB, including BAX and other significantly downregulated proteins. (D) SON depicting nodes around TNF including BCL2L13 and other significantly downregulated. Gene products (nodes) are represented as standard IPA polygons and relationships with lines (edges) between nodes. Full lines indicate a direct interaction and dashed lines an indirect interaction. Intensity of the node color indicates the degree of regulation (SAL vs. KA) and relationship strength is inversely related to line length. Genes represented by uncolored nodes were not differentially expressed in our experiments and were integrated by the IPA knowledge database. Arrows represent activation while non-arrowed lines binding only.

Mentions: Global molecular protein networks were identified and visualized using Ingenuity Pathway analysis (IPA, Ingenuity® Systems; Supplementary Fig. 2A,D). These complex networks were reduced into smaller ones, using IPA’s focused gene function (Fig. 2 and Supplementary Fig. 2B–F), revealing one significantly overrepresented network (SON) containing the upregulated protein CLU (Fig. 2A). CLU is upregulated in reactive astrocytes and linked to cell survival27, involved in the regulation of postnatal neurogenesis28 and executes anti-apoptotic functions by interacting with BAX, blocking CytC release from mitochondria and caspase activation29. A second SON included the upregulated protein GFAP (Fig. 2B), linked to astrogliosis. Two others SONs containing upregulated proteins were identified around Nuclear Factor Kappa-B (NFkB) and TNF (Supplementary Figure 2B,C, respectively).


MicroRNA-124 and -137 cooperativity controls caspase-3 activity through BCL2L13 in hippocampal neural stem cells.

Schouten M, Fratantoni SA, Hubens CJ, Piersma SR, Pham TV, Bielefeld P, Voskuyl RA, Lucassen PJ, Jimenez CR, Fitzsimons CP - Sci Rep (2015)

Significantly overrepresented networks containing dysregulated proteins in the DG after KA-SE.(A) SON depicting nodes around NFkB, including CLU and other upregulated proteins. (B) SON depicting nodes around FOS, including GFAP and other significantly upregulated proteins. (C) SON depicting nodes around NFkB, including BAX and other significantly downregulated proteins. (D) SON depicting nodes around TNF including BCL2L13 and other significantly downregulated. Gene products (nodes) are represented as standard IPA polygons and relationships with lines (edges) between nodes. Full lines indicate a direct interaction and dashed lines an indirect interaction. Intensity of the node color indicates the degree of regulation (SAL vs. KA) and relationship strength is inversely related to line length. Genes represented by uncolored nodes were not differentially expressed in our experiments and were integrated by the IPA knowledge database. Arrows represent activation while non-arrowed lines binding only.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4513647&req=5

f2: Significantly overrepresented networks containing dysregulated proteins in the DG after KA-SE.(A) SON depicting nodes around NFkB, including CLU and other upregulated proteins. (B) SON depicting nodes around FOS, including GFAP and other significantly upregulated proteins. (C) SON depicting nodes around NFkB, including BAX and other significantly downregulated proteins. (D) SON depicting nodes around TNF including BCL2L13 and other significantly downregulated. Gene products (nodes) are represented as standard IPA polygons and relationships with lines (edges) between nodes. Full lines indicate a direct interaction and dashed lines an indirect interaction. Intensity of the node color indicates the degree of regulation (SAL vs. KA) and relationship strength is inversely related to line length. Genes represented by uncolored nodes were not differentially expressed in our experiments and were integrated by the IPA knowledge database. Arrows represent activation while non-arrowed lines binding only.
Mentions: Global molecular protein networks were identified and visualized using Ingenuity Pathway analysis (IPA, Ingenuity® Systems; Supplementary Fig. 2A,D). These complex networks were reduced into smaller ones, using IPA’s focused gene function (Fig. 2 and Supplementary Fig. 2B–F), revealing one significantly overrepresented network (SON) containing the upregulated protein CLU (Fig. 2A). CLU is upregulated in reactive astrocytes and linked to cell survival27, involved in the regulation of postnatal neurogenesis28 and executes anti-apoptotic functions by interacting with BAX, blocking CytC release from mitochondria and caspase activation29. A second SON included the upregulated protein GFAP (Fig. 2B), linked to astrogliosis. Two others SONs containing upregulated proteins were identified around Nuclear Factor Kappa-B (NFkB) and TNF (Supplementary Figure 2B,C, respectively).

Bottom Line: Adult neurogenesis continuously contributes new neurons to hippocampal circuits and the programmed death of a subset of immature cells provides a primary mechanism controlling this contribution.However, a possible interplay between this factors remains largely unexplored.Within these networks, we report for the first time that the atypical BCL2 protein BCL2L13 controls caspase-3 activity and cytochrome C release in neural stem/progenitor cells.

View Article: PubMed Central - PubMed

Affiliation: Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, SciencePark 904, 1098XH, Amsterdam, The Netherlands.

ABSTRACT
Adult neurogenesis continuously contributes new neurons to hippocampal circuits and the programmed death of a subset of immature cells provides a primary mechanism controlling this contribution. Epileptic seizures induce strong structural changes in the hippocampus, including the induction of adult neurogenesis, changes in gene expression and mitochondrial dysfunction, which may all contribute to epileptogenesis. However, a possible interplay between this factors remains largely unexplored. Here, we investigated gene expression changes in the hippocampal dentate gyrus shortly after prolonged seizures induced by kainic acid, focusing on mitochondrial functions. Using comparative proteomics, we identified networks of proteins differentially expressed shortly after seizure induction, including members of the BCL2 family and other mitochondrial proteins. Within these networks, we report for the first time that the atypical BCL2 protein BCL2L13 controls caspase-3 activity and cytochrome C release in neural stem/progenitor cells. Furthermore, we identify BCL2L13 as a novel target of the cooperative action of microRNA-124 and microRNA-137, both upregulated shortly after seizure induction. This cooperative microRNA-mediated fine-tuning of BCL2L13 expression controls casp3 activity, favoring non-apoptotic caspase-3 functions in NSPC exposed to KA and thereby may contribute to the early neurogenic response to epileptic seizures in the dentate gyrus.

No MeSH data available.


Related in: MedlinePlus